Phosphoinositide 3-OH Kinase Inhibition Prevents Ventilation-induced Lung Cell Activation (original) (raw)
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Respiratory Physiology & Neurobiology, 2002
We investigated the potential inflammatory reaction induced by mechanical ventilation (MV) using 10 ml/kg tidal volume and no positive end-expiratory pressure (PEEP) in control (C, n= 8), spontaneously breathing (SB, n =12) and mechanically ventilated (MV, n= 12) rabbits with normal lungs. After 6 h (MV and SB groups) or immediately (C group), lungs were removed for measurement of wet-to-dry (W/D) weight ratio and for bronchoalveolar lavage (BAL). Pulmonary mechanics were also studied. MV animals developed a modest but significant (P B 0.01) impairment of arterial blood oxygenation and had higher W/D lung weight ratio than C ones. In MV group, BAL macrophage count was greater (PB0.05) than in SB one. MV induced an upregulation of MCP-1, TNF-a, and IL-1b gene transcription (mRNAs), without significant elevation of the corresponding protein cytokines in the BAL supernatant, except for MCP-1 (PB 0.05). These data suggest that MV, even using moderate tidal volume, elicits a pro-inflammatory stimulus to the lungs.
Intensive Care Medicine, 2010
Purpose The goal of the study was to compare the effects of different assisted ventilation modes with pressure controlled ventilation (PCV) on lung histology, arterial blood gases, inflammatory and fibrogenic mediators in experimental acute lung injury (ALI). Methods Paraquat-induced ALI rats were studied. At 24 h, animals were anaesthetised and further randomized as follows (n = 6/group): (1) pressure controlled ventilation mode (PCV) with tidal volume (V T) = 6 ml/kg and inspiratory to expiratory ratio (I:E) = 1:2; (2) three assisted ventilation modes: (a) assist-pressure controlled ventilation (APCV1:2) with I:E = 1:2, (b) APCV1:1 with I:E = 1:1; and (c) biphasic positive airway pressure and pressure support ventilation (BiVent + PSV), and (3) spontaneous breathing without PEEP in air. PCV, APCV1:1, and APCV1:2 were set with P insp = 10 cmH2O and PEEP = 5 cmH2O. BiVent + PSV was set with two levels of CPAP [inspiratory pressure (P High = 10 cmH2O) and positive end-expiratory pressure (P Low = 5 cmH2O)] and inspiratory/expiratory times: T High = 0.3 s and T Low = 0.3 s. PSV was set as follows: 2 cmH2O above P High and 7 cmH2O above P Low. All rats were mechanically ventilated in air and PEEP = 5 cmH2O for 1 h. Results Assisted ventilation modes led to better functional improvement and less lung injury compared to PCV. APCV1:1 and BiVent + PSV presented similar oxygenation levels, which were higher than in APCV1:2. Bivent + PSV led to less alveolar epithelium injury and lower expression of tumour necrosis factor-α, interleukin-6, and type III procollagen. Conclusions In this experimental ALI model, assisted ventilation modes presented greater beneficial effects on respiratory function and a reduction in lung injury compared to PCV. Among assisted ventilation modes, Bi-Vent + PSV demonstrated better functional results with less lung damage and expression of inflammatory mediators.
Journal of Applied Physiology, 2001
Mechanical ventilation of isolated septic rat lungs: effects on surfactant and inflammatory cytokines. J Appl Physiol 91: 811-820, 2001.-The effects of mechanical ventilation (MV) on the surfactant system and cytokine secretion were studied in isolated septic rat lungs. At 23 h after sham surgery or induction of sepsis by cecal ligation and perforation (CLP), lungs were excised and randomized to one of three groups: 1) a nonventilated group, 2) a group subjected to 1 h of noninjurious MV (tidal volume ϭ 10 ml/kg, positive end-expiratory pressure ϭ 3 cmH 2O), or 3) a group subjected to 1 h of injurious MV (tidal volume ϭ 20 ml/kg, positive end-expiratory pressure ϭ 0 cmH 2O). Nonventilated sham and CLP lungs had similar compliance, normal lung morphology, surfactant, and cytokine concentrations. Injurious ventilation decreased compliance, altered surfactant, increased cytokines, and induced morphological changes compared with nonventilation in sham and CLP lungs. In these lungs, the surfactant system was similar in sham and CLP lungs; however, tumor necrosis factor-␣ and interleukin-6 levels were significantly higher in CLP lungs. We conclude that injurious ventilation altered surfactant independent of sepsis and that the CLP lungs were predisposed to the secretion of larger amounts of cytokines because of ventilation.
Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases, 2004
To evaluate the effect of lung protective ventilation strategy on pulmonary inflammatory response in acute respiratory distress syndrome (ARDS). The ARDS rabbit model was duplicated by saline alveolar-lavage. The rabbits were divided into six groups: (1) normal control group (N group); (2) ARDS group (M group); (3) low-volume with best end-expiratory pressure (PEEP, A group) group: tidal volume (V(T)) 6 ml/kg, PEEP 2 cm H(2)O greater than the pressure of lower inflection point in pressure-volume curve (P(LIP)); (4) normal-volume with best PEEP group (B group): V(T) 6 ml/kg, and PEEP P(LIP) + 2 cm H(2)O; (5) low-volume with high PEEP group (C group): V(T) 6 ml/kg, and PEEP 15 cm H(2)O; and (6) high-volume with zero PEEP group (D group): V(T) 20 ml/kg. Lung wet/dry weight ratios (W/D) were recorded to evaluate lung injury. After 4 h of ventilation, lung homogenates were prepared to detect nuclear factor-kappaB (NF-kappaB) activity by electrophoretic mobility gel shift assay (EMSA), tu...
Effects of ventilation strategy on distribution of lung inflammatory cell activity
Critical Care, 2013
Introduction: Leukocyte infiltration is central to the development of acute lung injury, but it is not known how mechanical ventilation strategy alters the distribution or activation of inflammatory cells. We explored how protective (vs. injurious) ventilation alters the magnitude and distribution of lung leukocyte activation following systemic endotoxin administration. Methods: Anesthetized sheep received intravenous endotoxin (10 ng/kg/min) followed by 2 h of either injurious or protective mechanical ventilation (n = 6 per group). We used positron emission tomography to obtain images of regional perfusion and shunting with infused 13 N[nitrogen]-saline and images of neutrophilic inflammation with 18 F-fluorodeoxyglucose (18 F-FDG). The Sokoloff model was used to quantify 18 F-FDG uptake (K i), as well as its components: the phosphorylation rate (k 3 , a surrogate of hexokinase activity) and the distribution volume of 18 F-FDG (F e) as a fraction of lung volume (K i = F e × k 3). Regional gas fractions (f gas) were assessed by examining transmission scans. Results: Before endotoxin administration, protective (vs. injurious) ventilation was associated with a higher ratio of partial pressure of oxygen in arterial blood to fraction of inspired oxygen (PaO 2 /FiO 2) (351 ± 117 vs. 255 ± 74 mmHg; P < 0.01) and higher whole-lung f gas (0.71 ± 0.12 vs. 0.48 ± 0.08; P = 0.004), as well as, in dependent regions, lower shunt fractions. Following 2 h of endotoxemia, PaO 2 /FiO 2 ratios decreased in both groups, but more so with injurious ventilation, which also increased the shunt fraction in dependent lung. Protective ventilation resulted in less nonaerated lung (20-fold; P < 0.01) and more normally aerated lung (14-fold; P < 0.01). K i was lower during protective (vs. injurious) ventilation, especially in dependent lung regions (0.0075 ± 0.0043/min vs. 0.0157 ± 0.0072/min; P < 0.01). 18 F-FDG phosphorylation rate (k 3) was twofold higher with injurious ventilation and accounted for most of the between-group difference in K i. Dependent regions of the protective ventilation group exhibited lower k 3 values per neutrophil than those in the injurious ventilation group (P = 0.01). In contrast, F e was not affected by ventilation strategy (P = 0.52). Lung neutrophil counts were not different between groups, even when regional inflation was accounted for. Conclusions: During systemic endotoxemia, protective ventilation may reduce the magnitude and heterogeneity of pulmonary inflammatory cell metabolic activity in early lung injury and may improve gas exchange through its effects predominantly in dependent lung regions. Such effects are likely related to a reduction in the metabolic activity, but not in the number, of lung-infiltrating neutrophils.
Murine mechanical ventilation stimulates alveolar epithelial cell proliferation
Experimental Lung Research, 2010
High tidal volume mechanical ventilation can cause inflammation and lung damage. Mechanical strain is also necessary for normal lung growth. The current work was performed to determine if mechanical ventilation with clinically utilized tidal volumes stimulates a proliferative response in the lung. Six-to 8-week-old C57/Bl6 mice, anesthetized with ketamine/xylozine, were ventilated for 6 hours with 10 mL/kg tidal volume, positive endexpiratory pressure (PEEP) 3cm H 2 O. Pulmonary function testing demonstrated decreased compliance within 3 hours of ventilation. Assessment of bronchoalveolar lavage (BAL) demonstrated no significant increase in lactate dehydrogenase, total lavagable cell number, or total protein after ventilation. There was evidence of inflammation in the lungs of ventilated mice, with an increased percentage of lymphocytes and neutrophils in BAL, and an increase in macrophage inflammatory protein (MIP)-2 and interleukin (IL)-1β message in lung tissue. Immunohistochemistry of inflation-fixed lungs demonstrated increased alveolar cell proliferation, as measured by both proliferating cell nuclear antigen and Ki67 staining. Dual staining confirmed that proliferating cells labeled with proSP-B, demonstrating that ventilation induces proliferation of alveolar type II cells. Ventilation did not increase apoptosis in alveolar type II cells, as measured by TUNEL staining. Ventilation at low tidal volumes leads to a mild inflammatory response and alveolar epithelial cell proliferation.
Journal of Applied Physiology, 2007
Lung morpho-functional alterations and inflammatory response to various types of mechanical ventilation (MV) have been assessed in normal, anesthetized, open-chest rats. Measurements were taken during protective MV [tidal volume (Vt) = 8 ml/kg; positive end-expiratory pressure (PEEP) = 2.6 cmH2O] before and after a 2- to 2.5-h period of ventilation on PEEP (control group), zero EEP without (ZEEP group) or with administration of dioctylsodiumsulfosuccinate (ZEEP-DOSS group), on negative EEP (NEEP group), or with large Vt (26 ml/kg) on PEEP (Hi-Vt group). No change in lung mechanics occurred in the Control group. Relative to the initial period of MV on PEEP, airway resistance increased by 33 ± 4, 49 ± 9, 573 ± 84, and 13 ± 4%, and quasi-static elastance by 19 ± 3, 35 ± 7, 248 ± 12, and 20 ± 3% in the ZEEP, NEEP, ZEEP-DOSS, and Hi-Vt groups. Relative to Control, all groups ventilated from low lung volumes exhibited histologic signs of bronchiolar injury, more marked in the NEEP and ZEE...
Effects of mechanical ventilation of isolated mouse lungs on surfactant and inflammatory cytokines
2001
Mechanical ventilation of the lung is an essential but potentially harmful therapeutic intervention for patients with acute respiratory distress syndrome. The objective of the current study was to establish and characterize an isolated mouse lung model to study the harmful effects of mechanical ventilation. Lungs were isolated from BalbC mice and randomized to either a nonventilated group, a conventionally ventilated group (tidal volume 7 mL. kg-1 , 4 cm positive endexpiratory pressure (PEEP)) or an injuriously ventilated group (20 mL. kg-1 , 0 cm PEEP). Lungs were subsequently analysed for lung compliance, morphology, surfactant composition and in¯ammatory cytokines. Injurious ventilation resulted in signi®cant lung dysfunction, which was associated with a signi®cant increase in pulmonary surfactant, and surfactant small aggregates compared to the other two groups. Injurious ventilation also led to a signi®cantly increased concentration of interleukin-6 and tumour necrosis factor-a in the lavage. It was concluded that the injurious effects of mechanical ventilation can effectively be studied in isolated mouse lung, which offers the potential of studying genetically altered animals. It was also concluded that in this model, the lung injury is, in part, mediated by the surfactant system and the release of in¯ammatory mediators.
American Journal of Respiratory and Critical Care Medicine, 1999
Model-based neuro-fuzzy control of FiO 2 for intensive care mechanical ventilation HF Kwok, GH Mills, M Mahfouf, DA Linkens P3 Comparison of closed with open tracheal aspiration system A Sanver, A Topeli, Y Çetinkaya, S Kocagöz, S Ünal P4 A laboratory assessment of the learning and retention of skills required to use the Combitube and Laryngeal Mask Airway by non-anaesthetists C Coles, C Elding, M Mercer P5 Pediatric airway exchange catheter can be a lifesaving device for the adult patients who have risk factors for difficult tracheal reintubation L Dosemeci, F Gurpinar, M Yilmaz, A Ramazanoglu P6 Cricothyroidotomy for elective airway management in critically ill trauma patients SM Wanek, EB Gagnon, C Rehm, RJ Mullins P7 Comparison of two percutaneous tracheostomy techniques I . Ö Akinci, P Ozcan, S Tug v rul, N Çakar, F Esen, L Telci, K Akpir P8 Percutaneous tracheostomy in patients with ARDS on HFOV S Shah, M Read, P Morgan P9 The dilatational tracheotomy -minimally-invasive, bed-side, inexpensive -but safe? MG Baacke, I Roth, M Rothmund, L Gotzen P10 Combination stenting for central airway stenosis P11 Ulcerative laryngitis in children admitted to intensive care M Hatherill, Z Waggie, L Reynolds, A Argent P12 Bronchial asthma in intensive care department: the factors influencing on exacerbation severity TA Pertseva, KE Bogatskaya, KU Gashynova P13 Severe BOOP M Mer, R Taylor, GA Richards P14 Facial continuous positive airway pressure therapy for cardiogenic pulmonary oedema: a study of its efficacy in an emergency department setting within the UK C Read, P16 Noninvasive positive pressure ventilation in patients with blunt chest trauma and acute respiratory failure S Milanov, M Milanov P17 Helium-oxygen (He-O 2 ) enhances oxygenation and increases carbon dioxide clearance in mechanically ventilated patients JAS Ball, R Cusack, A Rhodes, RM Grounds P18 Optimal method of flow and volume monitoring in patients mechanically ventilated with helium-oxygen (He-O 2 ) mixtures JAS Ball, A Rhodes, RM Grounds P19 Lessons learned from airway pressure release ventilation LJ Kaplan, H Bailey P20 Patient controlled pressure support ventilation D Chiumello, P Taccone, L Civardi, E Calvi, M Mondino, N Bottino, P Caironi P21 Impact of weaning failure in the evolution of patients under mechanical ventilation A Bruhn, P22 Abstract withdrawn P23 Rapid reduction of oxygenation index by employment of a recruitment technique in patients with severe ARDS GA Richards, H White, M Hopley P24 The effects of recruitment maneuver on oxygenation in primary and secondary adult respiratory distress syndrome S Tug v rul, N Çakar, IÖ Akinci, P Ergin Özcan, M Tug v rul, F Esen, L Telci, K Akpir Contents Available online http://ccforum.com/supplements/5/S1 Critical Care Vol 5 Suppl 1 Contents P25 Comparison of the P/V curve obtained by the supersyringe and the optoelectronic plethysmography D Chiumello, E Calvi, E Noe', L Civardi, E Carlesso, A Aliverti, R Dellacà P26 Assessment of static compliance and estimated lung recruitment as a tool for PEEP setting in ARDS patients P Dostal, V Cerny, R Parizkova P27 Positive end-expiratory pressure does not increase intraocular pressure in patients with intracranial pathology K Kokkinis, P Manolopoulou, J Katsimpris, S Gartaganis P28 Effects of lung recruitment and PEEP after CPB on pressure-absolute volume curves T Dyhr, A Larsson P29 The histopathological changes comparison in healthy rabbit lung ventilated with ZEEP, Sigh and PEEP Ç Yardimci, G Meyanci, H Öz, I Paksoy
Ventilation with high tidal volume induces inflammatory lung injury
Brazilian Journal of Medical and Biological Research, 2002
Mechanical ventilation with high tidal volumes (V T) has been shown to induce lung injury. We examined the hypothesis that this procedure induces lung injury with inflammatory features. Anesthetized male Wistar rats were randomized into three groups: group 1 (N = 12): V T = 7 ml/kg, respiratory rate (RR) = 50 breaths/min; group 2 (N = 10): V T = 21 ml/kg, RR = 16 breaths/min; group 3 (N = 11): V T = 42 ml/kg, RR = 8 breaths/min. The animals were ventilated with fraction of inspired oxygen of 1 and positive end-expiratory pressure of 2 cmH 2 O. After 4 h of ventilation, group 3, compared to groups 1 and 2, had lower PaO 2 [280 (range 73-458) vs 517 (range 307-596), and 547 mmHg (range 330-662), respectively, P<0.05], higher wet lung weight [3.62 ± 0.91 vs 1.69 ± 0.48 and 1.44 ± 0.20 g, respectively, P<0.05], and higher wet lung weight/dry lung weight ratio [18.14 (range 11.55-26.31) vs 7.80 (range 4.79-12.18), and 6.34 (range 5.92-7.04), respectively, P<0.05]. Total cell and neutrophil counts were higher in group 3 compared to groups 1 and 2 (P<0.05), as were baseline TNF-α concentrations [134 (range <10-386) vs 16 (range <10-24), and 17 pg/ml (range <10-23), respectively, P<0.05]. Serum TNF-α concentrations reached a higher level in group 3, but without statistical significance. These results suggest that mechanical ventilation with high V T induces lung injury with inflammatory characteristics. This ventilatory strategy can affect the release of TNF-α in the lungs and can reach the systemic circulation, a finding that may have relevance for the development of a systemic inflammatory response.